Cocaine is responsible for more serious intoxications and deaths than other illicit drug, yet no effective treatments for cocaine abuse are currently available. One strategy for developing effective anti-cocaine agents is to block cocaine's access to its target proteins. Of the myriad of sites through which cocaine can act, s receptors are a promising target for drug development. In our earlier funded project, we identified over two-dozen novel s receptor antagonists that prevent cocaine-induced convulsions and lethality in mice. The best of these antagonists even prevent death when administered after the onset of symptoms of a severe cocaine overdose. These compounds, as well as antisense oligodeoxynucleotides against sigma receptors, also attenuate cocaine-induced locomotor activity, suggesting that they can block both the behavioral toxic and psychomotor stimulant effects of cocaine. With the initially funded proposal demonstrating that antagonism of sigma receptors, especially the sigma1 subtype, prevents the acute behavioral effects of cocaine, it is now time to investigate other cocaine-related behaviors that are more relevant to addiction. Therefore, the goal of the present competitive renewal is to validate the hypothesis that antagonism of sigma1 receptors attenuates the rewarding properties of cocaine and to begin defining the mechanisms involved in this protective action. Therefore, the specific aims of the project are: 1) To confirm that antagonism of sigma1 receptors attenuates the rewarding properties of cocaine, 2) To identify the genes that contribute to the behavioral protective actions of sigma1 receptor antagonists, and 3) To identify the brain regions that are involved in the behavioral protective actions of sigma1 receptor antagonists. It is anticipated that the results of this project will facilitate the development of new and effective treatments for cocaine abuse.